Objectives 2/16, 11/15, 9/15, 2/15, 9/14, 5/14, 2/14, 2/12

Transcription

1 MEDICATION COVERAGE POLICY PHARMACY AND THERAPEUTICS ADVISORY COMMITTEE POLICY: Hepatitis C P&T DATE: 9/11/2018 CLASS: Infectious Diseases REVIEW HISTORY: 2/18, 12/17, 9/17, 5/17, LOB: Medi-Cal (month/year) 2/17, 12/16, 9/16, 5/16, 2/16, 11/15, 9/15, 2/15, 9/14, 5/14, 2/14, 2/12 Background There is an estimated 2.2 to 3.2 million persons who are chronically infected with the hepatitis C virus (HCV) in the United States. 1 However, about 50% are unaware that they are infected. 2 The first step towards improving health outcomes among persons with HCV infection and preventing transmission is to identify those with active infections. 3 The next step would be to treat those identified patients and reduce all-cause mortality and liver-related health adverse consequences, as evidenced by an SVR (sustained virologic response) that translates to achievement of a virologic cure. Obtaining SVR is associated with more than a 70% reduction in the risk of hepatocellular carcinoma, as well as a 90% reduction in the risk of liver-related mortality and liver transplantation. 4 Although there are current regimens available that show evidence of high SVR rates, they are complicated by the variable price of therapy (treatment of genotype 1 HCV infection based on HPSJ prices can range from $56,000 to $300,000 regardless of cirrhosis status). The California Department of Health Care Services (DHCS) assists with these high costs by providing a set payment per week of treatment that follows their policies on the management and treatment of chronic Hepatitis C. However, as a managed care organization, we want to ensure that regimens being used are not only safe and recommended by guidelines, but cost effective as well. Objectives Summarize DHCS policy for Hepatitis C treatment (refer to appendix 1 for full policy) Define commonly used terminology (e.g. level of evidence, IFN ineligible, treatment experienced) Review history of Hepatitis C agents, their corresponding serious adverse events, and specific criteria necessary for erythropoietin use in Hepatitis C treatment related anemia Summarize American Association for the Study of Liver Diseases (AASLD) combination regimens with genotypes they can or cannot be used in Summarize AASLD recommendations for renal dosing adjustments and patients with concomitant HIV infections Summarize criteria that must be met for initial and continued coverage of Hepatitis C agents Analyze utilization of Hepatitis C agents Compare and analyze safety, efficacy, costs, and levels of evidence for agents recommended by AASLD guidelines for Hepatitis C per genotype, treatment experience, cirrhosis presence/type, and liver transplant status Review HPSJ preferred treatment regimens for Hepatitis C per genotype, treatment experience, and cirrhosis presence/type, and liver transplant status CA Department of Health Care Services Hepatitis C Policy Key Points 5 Treatment considerations, choice of regimen, and monitoring for hepatitis C virus infected patients will be based off of AASLD guidelines. Guidelines apply to all new FDA approved drugs and AASLD approved regimens. If a regimen is more cost effective and has either equivalent or better levels of evidence in the specific patient population, then we can ask the provider to substitute to that regimen. Coverage Policy Infectious Diseases - Hepatitis C

2 Definitions A. Level of Evidence 6 Classification Description Class I Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnostic evaluation, procedure, or treatment Class IIa Weight of evidence and/or opinion is in favor of usefulness and efficacy Class IIb Usefulness and efficacy are less well established by evidence and/or opinion Class III Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful Level of Description Evidence Level A* Data derived from multiple randomized clinical trials, meta-analyses, or equivalent Level B* Data derived from a single randomized trial, nonrandomized studies, or equivalent Level C Consensus opinion of experts, case studies, or standard of care *Due to it not being ethical or practical to test IFN-sparing HCV treatments in some situations, hence when those instances arise, the panel members considered the evidence as equivalent to a randomized controlled trial for levels A or B if a single pre-determined, FDA-approved equivalency was established. B. Serious Adverse Event (SAE) 7 Per the FDA Safety Information and Adverse Event Reporting Program, a serious adverse event (SAE) is labeled as such when the patient outcomes can lead to the following: Death Life-threatening Hospitalization Disability or permanent damage Congenital anomalies or birth defects Intervention to prevent permanent impairment or damage Any other important medical events such as allergic bronchospasm or serious blood dyscrasias C. Peginterferon alfa ineligible (IFN ineligible) 8 Intolerance to IFN Autoimmune hepatitis and other autoimmune disorders Hypersensitivity to PEG or any of its components Decompensated hepatic disease Major uncontrolled depressive illness A baseline neutrophil count below 1500/µL, a baseline platelet count below 90,000 µl or baseline hemoglobin below 10 g/dl A history of preexisting cardiac disease Coverage Policy Infectious Diseases - Hepatitis C

3 D. Child Turcotte Pugh (CTP) Classification of Severity of Cirrhosis 8 Class A Class B Class C Total points Factor 1 Point 2 Points 3 Points Total bilirubin (µmol/l) < >50 Serum albumin (g/l) > <28 Prothrombin time/international normalized ratio < >2.30 Ascites None Mild Moderate to Severe Hepatic encephalopathy None Grade I II (or suppressed Grade III IV (or with medication) refractory) E. Other commonly used terms 8 Terminology Definition IFN eligible Persons who do not meet criteria to be IFN ineligible Treatment Naïve Persons who have not received any prior treatment for Hepatitis C Persons who have received prior treatment for Hepatitis C. Specific Treatment Experienced treatments they have been exposed to are with the correlating recommended regimens in Appendix 2. Sustained Virologic Continued absence of detectable HCV RNA at least 12 weeks after Response (SVR) completion of therapy Equivalent to protease inhibitors: Boceprevir, Telaprevir, Simeprevir, Direct-acting antiviral Paritaprevir, Grazoprevir, Elbasvir, etc. Persons with moderate or severe hepatic impairment as shown by Child Turcotte Pugh (CTP) class B or C, and who may or may not be Decompensated cirrhosis candidates for liver transplantation, including those with hepatocellular carcinoma Medications for Hepatitis C Approval Brand Generic Route Copegus, Ribasphere Coverage Policy Infectious Diseases - Hepatitis C Serious Adverse Events (#) Ribavirin Oral (4-6) Birth defects/fetal death, avoid use in pregnancy Anemia with fatal or nonfatal MI Hepatic failure and death Severe hypersensitivity reactions Pulmonary disorders Severe depression and suicidal ideations Autoimmune and infectious disorders Bone marrow suppression with azathioprine Growth impairment in pediatrics Pegasys Peginterferon alfa-2a IM (1) Neuropsychiatric reactions Cardiovascular disorders Bone marrow suppression Autoimmune and endocrine disorders Ophthalmologic disorders Hepatic decompensation in cirrhotic patients, exacerbation in hepatitis B Pulmonary disorders Infections (bacterial, viral, fungal)

4 Colitis and pancreatitis Hypersensitivity and serious skin reactions Growth impairment in pediatrics Peripheral neuropathy with telbivudine Incivek Telaprevir Oral (6) Anemia Serious skin reactions Rash Victrelis Boceprevir Oral (12) Anemia Neutropenia Olysio Simeprevir Oral (1) Bradycardia with Sovaldi, amiodarone Hepatic decompensation/hepatic failure Photosensitivity Rash Sovaldi Sofosbuvir Oral (1) Bradycardia with amiodarone Viekira Pak Paritaprevir/Ritonavir /Ombitasvir + Dasabuvir Oral (4) Increased risk of ALT elevation Hepatic decompensation/ hepatic failure in patients with cirrhosis Harvoni Sofosbuvir/Ledipasvir Oral (1) Bradycardia with amiodarone Technivie Paritaprevir/Ritonavir Oral (2) /Ombitasvir Increased risk of ALT elevation Hepatic decompensation/ hepatic failure in patients with cirrhosis Daklinza Daclatasvir Oral (1) Bradycardia with Sovaldi, amiodarone Zepatier Elbatasvir/Grazoprevir Oral (1) Increased risk of ALT elevation Contraindicated with CTP Class B or C Epclusa Sofosbuvir/Velpatasvir Oral (1) Bradycardia with amiodarone Viekira XR Paritaprevir/Ritonavir /Ombitasvir + Dasabuvir Vosevi Sofosbuvir/Velpatasvir /Voxilaprevir Mavyret Glecaprevir/ Pibrentasvir Oral (3) Oral (1) Oral (3) *No longer recommended for use in Hepatitis C treatment by AASLD guidelines Increased risk of ALT elevation Hepatic decompensation/ hepatic failure in patients with cirrhosis Contraindicated in patients taking Rifampin Risk of Hepatitis B Reactivation Bradycardia with amiodarone Contraindicated in patients with severe hepatic impairment (CTP Class C), not recommended for use in CTP Class B Coadministration with Atazanivr and Rifampin Risk of Hepatitis B Reactivation Pipeline Medications for Hepatitis C 30 Proposed Release Date/Status Coverage Policy Infectious Diseases - Hepatitis C Drug Company MOA Possible Indication Frequency of Dosing No current pipeline drugs for Hepatitis C. Merck and Janssen have discontinued drug development for the listed combinations. GT 1, 2, and x 8, 12, 16, Phase II Grazoprevir + MK MK-8408 Merck or 24 weeks Phase II Simeprevir + odalasvir + ALS-335 Janssen and Achillion PoI = polymerase inhibitor; PI = protease inhibitor; GT = genotype NS3/4A PI + NS5A inhibitor + NS5B PoI GT 1 x 6 weeks

5 Medications for Hepatitis C by Mechanism of Action NS5B RNA Polymerase Inhibitor NS5A Protein Inhibitor ALS-335 Dasabuvir MK-3682 Sofosbuvir Velpatasvir Odalasvir Elbasvir Ombitasvir MK-8408 Pibrentasvir Ledipasvir Daclatasvir NS3/4A Protease Inhibitor Interferons RNA/DNA replication inhibitor Voxilaprevir Glecaprevir Peginterferon Ribavirin Sovaprevir Boceprevir Alfa-2a Grazoprevir Simeprevir Peginterferon Paritaprevir Telaprevir Alfa-2b Erythropoietin Stimulating Agents (ESA) in Hepatitis C Treatment Related Anemia According to the 2016 AASLD Guidelines, for patients taking Ribavirin and have a history of cardiovascular disease and a hemoglobin (Hgb) level below 10 g/dl, a dose reduction to 600 mg/day of Ribavirin is recommended in symptomatic or clinically indicated patients. 8 Discontinuation of Ribavirin is recommended for those with hemoglobin levels below 8.5 g/dl. 8 Reductions of Ribavirin dosing in 200 mg decrements towards a 600 mg/day dose did not appear to affect or compromise SVR rates. 19, 20 In the case that a dose reduction or discontinuation of Ribavirin does not help raise the hemoglobin levels back to 10 g/dl at the 2 week re-assessment, the addition of erythropoietin or darbepoetin at the lowest ESA dose sufficient to alleviate symptoms is suggested. 21, 22 There is no optimal hemoglobin level for patients with hepatitis C, but reducing or interrupting the ESA dose once hemoglobin levels exceed 10 g/dl is recommended to prevent the increased risks of death and other serious cardiovascular adverse events. 9, 23, 24 Also, if the hemoglobin rises too rapidly (e.g. more than 1g/dL in any 2-week period), then a reduction of the ESA dose is suggested to reduce the rapid response. 9, 23, 24 Coverage Criteria for ESA in Hepatitis C Treatment Related Anemia o Initial approval: Patient must meet all of the following criteria: [1] Treatment regimen that includes Ribavirin, with or without peginterferon [2] Documentation of a Hgb level <8.5 g/dl OR of a Hgb level <10 g/dl two weeks after dose reduction of ribavirin to 600 mg/day Approvals will be for a one-time fill, two weeks at a time. o Continuation: Patient must meet all of the following criteria: [1] Documentation of a Hgb level <10 g/dl after two weeks of prior ESA use [2] Rise in hemoglobin is no more than 1 g/dl from the level two weeks prior Different Drug Combination Regimens by AASLD 8 Coverage Policy Infectious Diseases - Hepatitis C RECOMMENDED REGIMENS Abbreviation Generic Name(s) Brand Name(s) Genotypes Monthly Cost

6 DCV + SOF Daclatasvir + Sofosbuvir Daklinza + 1a, 1b, 2, 3 $48, Sovaldi LDV-SOF Sofosbuvir/Ledipasvir Harvoni 1a, 1b, 4, 5, 6 $32, PrO Paritaprevir/Ritonavir/Ombitasvir Technivie 4 $25, PrOD Paritaprevir/Ritonavir/Ombitasvir Viekira Pak 1a, 1b $27, Dasabuvir PrOD Paritaprevir/Ritonavir/Ombitasvir Viekira XR 1a, 1b $28, Dasabuvir SOF Sofosbuvir Sovaldi 2, 3, 4 $27, SMV + SOF Simeprevir + Sofosbuvir Olysio + 1a, 1b $49, Sovaldi ELB-GRZ Elbasvir/Grazoprevir Zepatier 1a, 1b, 4 $18, SOF-VEL Sofosbuvir/Velpatasvir Epclusa Pangenotype $25, ELB-GRZ + Elbasvir/Grazoprevir + Sofosbuvir Zepatier + 3 $46, SOF Sovaldi SOF-VEL-VOX Sofosbuvir/Velpatasvir/Voxilaprevir Vosevi 2, 3 $29, GLE-PIB Glecaprevir/Pibrentasvir Mavyret 1a, 1b, 2, 3, 4, 5, 6 $15, RBV can be added onto any of the above regimens, varies per treatment regimen needed RBV Ribavirin (1,000 mg/day if <75 kg or 1,200 mg/day if 75 kg) Copegus, Ribasphere, Ribapak All $ NOT RECOMMENDED REGIMENS Generic Name(s) Genotypes Sofosbuvir + Ribavirin 1 Peginterferon alfa + Ribavirin ALL Peginterferon alfa alone ALL Ribavirin alone ALL DAA alone ALL Peginterferon alfa + Ribavirin + only one DAA 1, 2, 3 Peginterferon alfa + Ribavirin + Simeprevir 4, 5, 6 Telaprevir or Boceprevir based 2, 3, 4, 5, 6 Ledipasvir based 2 Simeprevir based (no IFN) 1, 3 Peginterferon alfa + Ribavirin + Sofosbuvir 2, 3, 4, 5, 6 DAA = direct-acting antiviral Summary of Recommendations for Renal Dose Adjustments CrCl CrCl CrCl <30 ml/min, without cirrhosis, urgency to treat/retreat Agents ml/min ml/min is high, renal transplant is not an immediate option Coverage Policy Infectious Diseases - Hepatitis C

7 DCV Standard Standard LDV-SOF Standard Standard PrO Standard Standard PrOD Standard Standard Genotype 1a Preferred w/rbv Genotype 1b Preferred Genotype 4 SOF Standard Standard SMV Standard Standard ELB-GRZ Standard Standard Preferred Preferred Preferred SOF/VEL Standard Standard Peg-IFN* RBV 180 µg/day Standard 180 µg/day Alternate 200 mg, 400 mg Genotype 2, 3, 5 or 6 RBV intolerant or ineligible N/A N/A N/A Preferred N/A 200 mg TIW or QD *CrCl <30 ml/min: 135 µg/day, ESRD with HD: 135 µg/week Dose Adjust Co-infection with HIV Please refer to the Hepatitis C treatment guidelines ( as well as the HIV/AIDS practice guidelines ( for recommendations in dose adjustments for patients with HIV/HCV co-infection. Any recommendations or changes shall be done in collaboration with the HIV practitioner. Treatment of Adolescents Ages 12 to 17 years 32 As of April 7, 2017 Harvoni and Sovaldi were FDA approved for hepatitis C treatment in children ages 12 to 17. Harvoni is indicated for Genotype 1, 4, 5, 6 without cirrhosis or mild cirrhosis, aged 12 or older, weighing at least 77 pounds (35 kg) Sovaldi with Ribavirin is indicated for Genotype 2 or 3 without cirrhosis or mild cirrhosis, aged 12 or older, weighing at least 77 pounds (35 kg) Documentation Requirements Prior to, During, and After Therapy 8 Pre-Treatment Initiation Criteria o Meets at least one of the identification requirements per the latest DHCS Hepatitis C Treatment Policy (refer to Appendix 1) o Is 18 years of age or older o Has been evaluated for readiness to initiate treatment and will adhere to the treatment o Does not have a life expectancy less than 12 months o Laboratory testing Any time prior to initiating therapy (required) Documentation of baseline hepatitis C virus-rna level Documentation of hepatitis C virus genotype and subtype Serum pregnancy test in woman of childbearing age if RBV is also being initiated Coverage Policy Infectious Diseases - Hepatitis C

8 o Screening at baseline and continuously throughout treatment for evidence of current or prior Hepatitis B infection is required. 31 o This is due to cases of hepatitis B reactivation occurring within 4 to 8 weeks of treatment resulting in serious liver problems or death. 31 Within 12 weeks prior to starting antiviral therapy Complete blood count Baseline hepatic function panel (albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels) Glomerular filtration rate If requested regimen contains any HCV NS3 protease inhibitor (e.g. paritaprevir, simeprevir, grazoprevir), patient has history of decompensated liver disease or current CTP score of 7 or greater, then patient should NOT receive treatment due to lack of safety data. Also, if the CTP score is 5 or 6 and the person receiving treatment cannot be closely monitored for laboratory or clinical symptoms during treatment, then treatment with the requested regimen will be modified to an alternative preferred regimen. If requested regimen is for Viekira Pak, Viekira XR, Technivie, or Zepatier, ensure that the patient is CTP class A and that close monitoring of total and direct bilirubin and transaminase levels occur every 1 to 2 weeks for the first 4 weeks is possible. If drug-induced liver injury is present then discontinuation is recommended, but if patient is tolerating and there are not signs/symptoms of liver injury, then continuous lab monitoring without discontinuation is recommended. Genotype 1a infected individuals: If requesting for Zepatier, NS5A Resistance Genetic Testing MUST be performed and results provided. If no test is performed then an alternative preferred regimen will be recommended. If requesting for Daklinza and patient has cirrhosis, NS5A Resistance Testing is recommended. Due to baseline NS5A resistance-associated variants (RAV - positions M28, Q30, L31, and Y93 in genotype 1a) being strong pre-treatment predictors of treatment outcome for certain regimens, testing for these RAVs before deciding the treatment regimen is recommended. Genotype 3 infected individuals requesting Epclusa: RAV testing for Y93H (NS5A testing) is recommended in treatment naïve/cirrhotic and treatment experienced/non-cirrhotic patients Ribavirin should be included if test returns positive. o In comparing SVR12, rates went from 97% without baseline polymorphisms to 88% with Y93H polymorphism. If patient is treatment experienced with SOF+RBV and do not require urgent treatment, recommended to defer treatment pending new future regimens. If retreatment is urgent, Epclusa x 24 weeks may be considered. Any additional information that would support the use of an alternate regimen from HPSJ preferred regimens Examples Coverage Policy Infectious Diseases - Hepatitis C

9 o o Patient meets criteria for being IFN ineligible Contraindications to preferred regimens per individual package inserts If requesting for retreatment, provide all above information as well as past treatment history. Initial approval will last 6 weeks with a quantity limit up to 28 days of therapy per fill. During Treatment Criteria for Continuation or Discontinuation of Therapy o Week 4 of Treatment Quantitative HCV viral load must be provided before continuation of therapy may be approved. If detectable, repeat quantitative HCV RNA viral load at week 6 of treatment is required before continuation of therapy may be approved. If quantitative HCV viral load has increased by greater than 10-fold (>1log 10 IU/mL) at week 6 of treatment or thereafter, DISCONTINUATION of HCV treatment is recommended. If the HCV RNA test result is still elevated but is lower than 10-fold, no recommendations can be provided on whether to stop or extend therapy at this time. If on Viekira Pak, Viekira XR, Technivie, or Zepatier therapy, complete hepatic function panel must be provided as well. Evidence of missed medical appointments related to hepatitis C virus or lack of adherence may result in denial of treatment reauthorization. Approvals will last to the end of 12 weeks of treatment with a quantity limit up to 28 days of therapy per fill. o Week 12 of Treatment If treatment completion at week 12, Quantitative HCV viral load will be requested. If treatment requires 24 weeks of treatment, Quantitative HCV viral load must be provided before continuation of therapy may be approved. Approvals will last to the end of 24 weeks of treatment with a quantity limit up to 28 days of therapy per fill. o Week 24 of Treatment Quantitative HCV viral load will be requested. After Treatment Criteria for Follow-up Quantitative HCV viral load 12 weeks after the completion of treatment is required and must be provided. Coverage Policy Infectious Diseases - Hepatitis C

10 HPSJ Preferred Hepatitis C Treatment Regimens a a Refer to Appendix 2 and 3 for further details on each regimen Note: Viekira XR is formulary and follows preferred regimen listing as Viekira Pak for each treatment group. Genotype 1a, Treatment Naive, Non-cirrhotic 1 Mavyret 99% 8 $31, I A 2 Zepatier 92% 12 $55, I A 3 Epclusa 98% 12 $76, I A 4 Viekira Pak & Ribavirin 95-97% 12 $82, I A 5 Harvoni 94-98% 12 $96, I A 6 Olysio & Sovaldi 97% 12 $148, I A 7 Harvoni 95% 8 $64, I B 8 Daklinza & Sovaldi 96% 12 $145, I B 9 Zepatier 100% 16 $74, IIa B NS5A Resistance Testing must be negative to be approved for this regimen All agents have comparable efficacy. As there is no specific preferred regimen among the class I, level A recommended regimens, Mavyret will be 1 st preferred due to overall safety, efficacy, and cost. As observed within each of the respective trials, risk of adverse events was minimal and was only slightly increased due to the addition of Ribavirin. Viekira Pak has an increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning Viekira Pak. Zepatier also notes this risk of liver injury. The package inserts also clearly state that both Viekira Pak and Zepatier are contraindicated for use in CTP class B or C. Patients in this specific treatment group are non-cirrhotic, hence this adverse event does not affect the order of the regimens as much. The preference for Viekira Pak with Ribavirin over Harvoni may be an increase in pill burden but it is more a matter of inconvenience. If an alternate regimen from the preferred is requested then it will be considered on a case by case basis. Zepatier in genotype 1a patients has been noted to have a significantly reduced SVR-12 if NS5A resistance is present at baseline and would require prolonged treatment for 16 weeks along with the addition of Ribavirin. Harvoni x 8 weeks is only a viable option if patient meets the following criteria: Genotype 1, treatment naïve, noncirrhotic, non-black, HIV-uninfected, and baseline HCV RNA below 6 million IU/mL(Class I, Level B) AND patient must not be able to receive either 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th preferred therapies due to a level B evidence rating. Coverage Policy Infectious Diseases - Hepatitis C Page 10

11 Genotype 1a, Treatment Naive, Compensated Cirrhotic 1 Mavyret 98% 12 $47, I A 2 Zepatier 97% 12 $55, I A 3 Epclusa 99% 12 $76, I A 4 Harvoni 97-99% 12 $96, I A 5 Viekira Pak & Ribavirin 92-95% 24 $164, I A 6 Zepatier 100% 16 $74, IIa B NS5A Resistance Testing must be negative to be approved for this regimen For this treatment group, Mavyret has shown to be the most cost effective regimen. It shows comparable efficacy to the Zepatier and Epclusa, as well as to Harvoni which shows slightly better efficacy than Viekira Pak with Ribavirin. The 1 st to 4 th preferred regimens show shorter duration of treatment, lower overall cost, less risk of adverse events, and a high level of evidence. Viekira Pak with Ribavirin is the 5 th most cost effective regimen with its higher SVR rates, lower overall cost, and high level of evidence. Also taken into consideration was that Viekira Pak has recently updated its package insert to include increased risk of liver injury, in which the outcomes reported were mainly in patients with evidence of advanced cirrhosis prior to beginning Viekira Pak. As per the package insert, Viekira Pak is contraindicated for use in CTP class B or C, hence it can only be initiated if the patient is CTP class A. However, caution and frequent labs should occur in the initial month of treatment with Viekira Pak. Zepatier is also contraindicated in CTP Class B or C and is also known to have a risk of liver injury. As the sample size involved in determining the SVR-12 for this treatment group is higher than that used for Epclusa, Zepatier will remain the 2 nd preferred regimen, but if the patient has signs/symptoms of progression towards CTP Class B or C, then approval of the 3 rd preferred regimen can be considered if Mavyret cannot be used. Regimens containing Olysio and Sovaldi or Daklinza and Sovaldi are no longer recommended. Zepatier in genotype 1a patients has been noted to have a significantly reduced SVR-12 if NS5A resistance is present at baseline and would require prolonged treatment for 16 weeks along with the addition of Ribavirin. Genotype 1a, Treatment Experienced with PEG/RBV, Non-cirrhotic 1 Mavyret 99% 8 $31, I A 2 Zepatier 93-94% 12 $55, I A 3 Epclusa 100% 12 $76, I A 4 Viekira Pak & Ribavirin 96% 12 $82, I A 5 Harvoni 94% 12 $96, I A 6 Olysio & Sovaldi 95% 12 $148, I A 7 Daklinza & Sovaldi 83% 12 $145, I B 8 Zepatier & Ribavirin % 16 $74, IIa B NS5A Resistance Testing must be negative to be approved for this regimen All recommended regimens were preferred based on SVR-12 and levels of evidence, except Epclusa shows an SVR-12 of 100%. This is a marginal SVR-12 in comparison to Mavyret and therefore Mavyret was preferred due to shorter treatment duration, high efficacy, and lower overall cost. Review of the sample size for the Epclusa trial verifies that the treatment group is less than the Zepatier trial, and with consideration of overall cost and ease of administration, Epclusa was preferred over Viekira Pak with Ribavirin. Overall the first 3 preferred regimens have greater sample sizes in the trials used to obtain SVR-12 as compared to trials with Harvoni and Daklinza with Sovaldi. Viekira Pak has an increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning Viekira Pak. Zepatier also notes this risk of liver injury. The package inserts also clearly state that both Viekira Pak and Zepatier are contraindicated for use in CTP class B or C. Patients in this specific treatment group are non-cirrhotic, hence this adverse event does not affect the order of the regimens as much. The preference for Viekira Pak with Ribavirin over Harvoni may be an increase in pill burden but it is more a matter of inconvenience. If an alternate regimen from the preferred is requested then it will be considered on a case by case basis. Coverage Policy Infectious Diseases - Hepatitis C Page 11

12 Recommendations for the use of Daklinza were derived from a trial that was performed for 24 weeks and had a sample size of 21 patients. Also, the trial was for patient s treatment experienced with PI + PEG + RBV. But in patients with just treatment experience with PEG + RBV for 12 weeks, there is an even lower SVR-12 rate of just 83% which suggests that further direct studies are needed before its cost effectiveness can truly be discerned. Zepatier in genotype 1a patients has been noted to have a significantly reduced SVR-12 if NS5A resistance is present at baseline and would require prolonged treatment for 16 weeks along with the addition of Ribavirin. Genotype 1a, Treatment Experienced with PEG/RBV, Compensated Cirrhotic 1 Zepatier 93-95% 12 $55, I A 2 Epclusa 100% 12 $76, I A 3 Harvoni & Ribavirin 96% 12 $96, I A 4 Mavyret 98.9% 12 $47, I B 5 Zepatier & Ribavirin % 16 $74, I B NS5A Resistance Testing must be negative to be approved for this regimen Regimens with a Class I, Level A evidence are not specifically tiered in any order per AASLD guidelines. These regimens share similar efficacy as well. Overall, the final order of preferred regimens is based on overall cost and treatment duration. Hence, Zepatier is the first preferred regimen. It is important to note that Zepatier is contraindicated in CTP class B/C and are known to have an increased risk of liver injury within the initial month of treatment initiation. Although Harvoni does not have as significant a risk, it is the next preferred regimen after Epclusa due the addition of Ribavirin. Mavyret is fourth preferred due to decreased duration, high SVR-1, and lower overall cost compared to Zepatier with Ribavirin. Zepatier in genotype 1a patients has been noted to have a significantly reduced SVR-12 if NS5A resistance is present at baseline and would require prolonged treatment for 16 weeks along with the addition of Ribavirin. Genotype 1b, Treatment Naive, Non-cirrhotic 1 Mavyret 99% 8 $31, I A 2 Zepatier 95-99% 12 $55, I A 3 Epclusa 99% 12 $76, I A 4 Viekira Pak 98-99% 12 $82, I A 5 Harvoni 97-99% 12 $96, I A 6 Olysio & Sovaldi 97% 12 $148, I A 7 Harvoni 95% 8 $64, I B 8 Daklinza & Sovaldi 100% 12 $145, I B Treatment regimen preferences no longer match with Genotype 1a, treatment naïve, non-cirrhotic preferred regimens. This is due to the fact that Mavyret is highly cost effective and the sample size specific to 1a patients with Epclusa was higher than Zepatier, but for genotype 1b, the sample size of Epclusa was smaller than the Zepatier trials. The resulting preference in regimens were based on overall level of evidence, cost, similar efficacy, and similar treatment duration. Note that NS5A resistance testing is not necessary for Genotype 1b treatment regimens. Harvoni x 8 weeks is only a viable option if patient meets the following criteria: Genotype 1, treatment naïve, non-cirrhotic, non-black, HIV-uninfected, and baseline HCV RNA below 6 million IU/mL(Class I, Level B) AND patient must not be able to receive either 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th preferred therapies due to a level IB evidence rating. Coverage Policy Infectious Diseases - Hepatitis C Page 12

13 Genotype 1b, Treatment Naive, Compensated Cirrhotic 1 Mavyret 100% 12 $47, I A 2 Zepatier 99% 12 $55, I A 3 Epclusa 99% 12 $76, I A 4 Harvoni 97-99% 12 $96, I A 5 Viekira Pak 98-99% 12 $82, I A Overall preferences were based on levels of evidence, SVR-12, safety, and overall cost. Note that NS5A resistance testing is not necessary for Genotype 1b treatment regimens. Genotype 1b, Treatment Experienced with PEG/RBV, Non-cirrhotic 1 Mavyret 99% 8 $31, I A 2 Zepatier 93-94% 12 $55, I A 3 Epclusa 98% 12 $76, I A 4 Viekira Pak % 12 $82, I A 5 Harvoni 94% 12 $96, I A 6 Olysio & Sovaldi 95% 12 $148, I A 7 Daklinza & Sovaldi 83% 12 $145, I B Mavyret is the most cost effective regimen, showing a high efficacy and lower overall cost than all other recommended regimens for patients who have failed prior treatment with PEG + RBV. The sample size used to determine SVR-12 for Epclusa was much smaller than Zepatier, hence Zepatier s preference over Epclusa after comparing side effects, overall cost, and level of evidence. Viekira Pak and Zepatier have increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning treatment. The package inserts also clearly state that Viekira Pak and Zepatier are contraindicated for use in CTP class B or C. Patients in this treatment group are non-cirrhotic, hence the updated adverse event does not affect this treatment regimen. Due to similar SVR-12, levels of evidence, and treatment duration, preference of Harvoni over Olysio with Sovaldi was made due to lesser overall treatment cost. Genotype 1b, Treatment Experienced with PEG/RBV, Compensated Cirrhotic 1 Zepatier 93-95% 12 $55, I A 2 Epclusa 98% 12 $76, I A 3 Viekira Pak 100% 12 $82, I A 4 Harvoni & Ribavirin 96% 12 $96, I A 5 Mavyret 99% 12 $47, I B The sample size used to determine SVR-12 for Epclusa was much smaller than Zepatier, hence Zepatier s preference over Epclusa after comparing side effects, overall cost, and level of evidence. Zepatier and Viekira Pak have the possibility of a serious adverse event of liver injury within the first month of initiation, especially in patients with advanced cirrhosis. Zepatier and Viekira Pak are contraindicated in CTP class B or C and can only be initiated if the patient is CTP class A. Due to the cost effectiveness and lower pill burden of Zepatier, it is the preferred regimen over Viekira Pak and Harvoni with Ribavirin. Mavyret has a level of evidence of 1B making it the least preferred regimen in this treatment group. Coverage Policy Infectious Diseases - Hepatitis C Page 13

14 Genotype 1a or 1b, Treatment Experienced with Protease Inhibitor + PEG/RBV, Non-cirrhotic 1 Epclusa 100% 12 $76, I A 2 Harvoni 94% 12 $96, I A 3 Mavyret 92% 12 $47, IIa B 4 Zepatier & Ribavirin 93-96% 12 $55, IIa B 5 Zepatier & Ribavirin % 16 $74, IIa B NS5A Resistance Testing must be negative to be approved for this regimen in genotype 1A patients, or must be Genotype 1b All recommended regimens were preferred based on SVR-12, levels of evidence, pill burden, and lastly cost. Zepatier in genotype 1a patients has been noted to have a significantly reduced SVR-12 if NS5A resistance is present at baseline and would require prolonged treatment for 16 weeks along with the addition of Ribavirin. Genotype 1a or 1b, Treatment Experienced with Protease Inhibitor + PEG/RBV, Compensated Cirrhotic 1 Epclusa 100% 12 $76, I A 2 Harvoni with Ribavirin 94% 12 $96, I A 3 Mavyret 92% 12 $47, IIa B 4 Zepatier & Ribavirin 93-96% 12 $55, IIa B 5 Zepatier & Ribavirin % 16 $74, IIa B NS5A Resistance Testing must be negative to be approved for this regimen in genotype 1A patients, or must be Genotype 1b All recommended regimens were preferred based on SVR-12, levels of evidence, pill burden, and lastly cost. Zepatier in genotype 1a patients has been noted to have a significantly reduced SVR-12 if NS5A resistance is present at baseline and would require prolonged treatment for 16 weeks along with the addition of Ribavirin. Genotype 1a or 1b, Treatment Experienced with Sovaldi (Non-NS5A), Non-cirrhotic 1 Vosevi 97% 12 $89, I A 2 Mavyret 98% 12 $47, IIa B 3 Epclusa * 95% 12 $76, IIa B 4 Harvoni 100% 12 $96, IIa B For Genotype 1a patients only *For Genotype 1b patients only Vosevi is the solely level 1A recommended regimen and will be first preferred for genotype 1A patients that meet this treatment group. For genotype 1B patients, Mavyret will be preferred over Epclusa due to lower overall pill burden and higher SVR-12. Mavyret and Epclusa had overall low sample sizes hence the lower level of evidence. Harvoni and Ribavirin has 100% SVR-12 but requires use of Ribavirin and has more risks of adverse effects, hence it is least preferred. Coverage Policy Infectious Diseases - Hepatitis C Page 14

15 Genotype 1a or 1b, Treatment Experienced with Sovaldi (Non-NS5A), Compensated Cirrhotic 1 Vosevi 97% 12 $89, I A 2 Mavyret 98% 12 $47, IIa B 3 Epclusa * 95% 12 $76, IIa B For Genotype 1a patients only *For Genotype 1b patients only Vosevi is the solely level 1A recommended regimen and will be first preferred for genotype 1A patients that meet this treatment group. For genotype 1B patients, Mavyret will be preferred over Epclusa due to lower overall pill burden and higher SVR-12. Mavyret and Epclusa had overall low sample sizes hence the lower level of evidence. Genotype 1a or 1b, Treatment Experienced with NS5A-Inhibitor, Regardless of Cirrhosis 1 Vosevi % 12 $89, I A 2 Mavyret 94% 16 $63, IIa B Vosevi is the solely level 1A recommended regimen and will be first preferred for genotype 1A patients that meet this treatment group. Genotype 2, Treatment Naive, Non-cirrhotic 1 Mavyret 99% 8 $31, I A 2 Epclusa % 12 $76, I A 3 Daklinza & Sovaldi 100% 12 $145, IIa B Preferred regimens are based on levels of evidence in order to comply with DHCS policy. Genotype 2, Treatment Naive, Compensated Cirrhotic 1 Epclusa % 12 $76, I A 2 Mavyret 100% 12 $47, I B 3 Daklinza & Sovaldi 100% 12 $145, IIa B Preferred regimens are based on levels of evidence to comply with DHCS policy. Also noted that Mavyret clinical trials had a sample size that was low hence the lower level of evidence. Genotype 2, Treatment Experienced with PEG/RBV, Non-cirrhotic 1 Mavyret 98% 8 $31, I A 2 Epclusa % 12 $76, I A 3 Daklinza & Sovaldi 100% 12 $145, IIa B Preferred regimens are based on levels of evidence, duration of therapy, and overall cost effectiveness. Coverage Policy Infectious Diseases - Hepatitis C Page 15

16 Genotype 2, Treatment Experienced with PEG/RBV, Compensated Cirrhotic 1 Epclusa % 12 $76, I A 2 Mavyret 100% 12 $47, I B 3 Daklinza & Sovaldi 100% 12 $145, IIa B Preferred regimens are based on levels of evidence to comply with DHCS policy. Genotype 2, Treatment Experienced with Sovaldi, Regardless of Cirrhosis 1 Epclusa 97% 12 $76, I B 2 Mavyret % 12 $47, IIb B a Corresponds to persons treatment experienced with SOF + RBV + IFN eligible Preferred regimens are based on levels of evidence to comply with DHCS policy. Note that although Mavyret has a high SVR-12, the population specific to this treatment group within the trials was unclear, hence the lower level of evidence. Genotype 3, Treatment Naive, Non-cirrhotic 1 Mavyret 95% 8 $31, I A 2 Epclusa 98% 12 $76, I A 3 Daklinza & Sovaldi 67-97% 12 $145, I A Preferred regimens are based on levels of evidence to comply with DHCS policy as well as treatment duration, safety, and cost. Also, the 67% in SVR-12 for Daklinza with Sovaldi was found in non-cirrhotic genotype 3 patients with a NS5A Y93H polymorphism. For Daklinza regimens in genotype 3, it is suggested that a negative NS5A Y93H polymorphism would be required before further consideration of either regimen can occur. Genotype 3, Treatment Naive, Compensated Cirrhotic 1 Mavyret 100% 12 $47, I A 2 Epclusa 93% 12 $76, I A 3 Vosevi* 100% 12 $89, IIa B 4 Daklinza & Sovaldi 58-88% 24 $290, IIa B 5 Daklinza & Sovaldi & Ribavirin 58-88% 24 $290, IIa B Y93H polymorphism Testing must be negative to be approved for this regimen, if positive, addition of Ribavirin is necessary *Only if Y93H polymorphism is present Preferred regimens are based on levels of evidence to comply with DHCS policy. For both Epclusa and Daklinza regimens in genotype 3, it is suggested that a negative NS5A Y93H polymorphism would be required before further consideration of either regimen can occur. In cirrhotic patients with Y93H polymorphism, Epclusa regimens are recommended to have Ribavirin added or Vosevi can be used instead (note trial only involved 6 patients that would meet this treatment group). Coverage Policy Infectious Diseases - Hepatitis C Page 16

17 Genotype 3, Treatment Experienced with PEG/RBV, Non-cirrhotic 1 Epclusa 95% 12 $76, I A 2 Daklinza & Sovaldi 92-98% 12 $145, I A 3 Mavyret 96% 16 $63, IIa B 4 Vosevi 84% 12 $89, IIa B Y93H polymorphism Testing must be negative to be approved for this regimen, if positive, addition of Ribavirin is necessary Preferences were based on level of evidence to comply with DHCS policy, as well as SVR-12, and total cost. For both Epclusa and Daklinza regimens in genotype 3, it is suggested that a negative NS5A Y93H polymorphism would be required before further consideration of either regimen can occur. In cirrhotic patients with Y93H polymorphism, Epclusa regimens are recommended to have Ribavirin added. Also noted that the true appropriate length of therapy is still unclear for Mavyret treatment in this patient group, hence 16 weeks was deemed appropriate as an alternative regimen. Genotype 3, Treatment Experienced with PEG/RBV, Compensated Cirrhotic 1 Epclusa & Ribavirin 89% 12 $76, I B 2 Zepatier & Sovaldi 100% 12 $138, I B 3 Mavyret 96% 16 $63, IIa B 4 Vosevi 84% 12 $89, IIb B Preferences were based on level of evidence to comply with DHCS policy, SVR-12, and total cost. Please note that Zepatier with Sovaldi for 12 weeks is placed as the second preferred regimen in this treatment group due to a smaller sample size (half the size) used during trials in comparison to the study for Epclusa with Ribavirin. Genotype 3, Treatment Experienced with DAA, Regardless of Cirrhosis 1 Vosevi 96% 12 $89, I A 2 Vosevi with Ribavirin - 12 $89, IIa C Preferences were based on level of evidence to comply with DHCS policy. Note that Vosevi with Ribavirin is only intended for patients with treatment failure to NS5A inhibitor and cirrhosis. Genotype 4, Treatment Naive, Non-Cirrhotic 1 Mavyret 100% 8 $31, I A 2 Technivie & Ribavirin 100% 12 $75, I A 3 Epclusa 100% 12 $76, I A 4 Zepatier 93-95% 12 $55, IIa B 5 Harvoni % 12 $96, IIa B Coverage Policy Infectious Diseases - Hepatitis C Page 17

18 Preferences were based on level of evidence to comply with DHCS policy, as well as SVR-12, safety, and total cost. Technivie and Zepatier have increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning treatment. The package inserts also clearly state that Technivie and Zepatier are contraindicated for use in CTP class B or C, hence Technivie in this treatment group can be initiated if the patient is non-cirrhotic/ctp class A. Vigilance in evaluating contraindications for each individual agent is necessary in ensuring the safety of patients taking HCV regimens. Zepatier is preferred over Harvoni due to cost effectiveness. Genotype 4, Treatment Naive, Compensated Cirrhotic 1 Epclusa 100% 12 $76, I A 2 Technivie & Ribavirin 97% 12 $75, I A 3 Mavyret 100% 12 $47, I B 4 Zepatier 100% 12 $55, IIa B 5 Harvoni % 12 $96, IIa B Preferences were based on level of evidence to comply with DHCS policy and total cost. SVR-12 for Epclusa, as well as sample size for the SVR-12 rate, is higher than Technivie with Ribavirin and hence has been placed as the preferred regimen. Technivie and Zepatier have increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning treatment. The package inserts also clearly state that Technivie and Zepatier are contraindicated for use in CTP class B or C, hence Technivie in this treatment group can be initiated if the patient is non-cirrhotic/ctp class A. Vigilance in evaluating contraindications for each individual agent is necessary in ensuring the safety of patients taking HCV regimens. Note that Mavyret regimen although less costly has lower level of evidence due to SVR-12 results are from a mixed sample size of 16 treatment naïve- and -experienced genotype 4 patients with compensated cirrhosis. Zepatier is preferred over Harvoni due to cost effectiveness. Genotype 4, Treatment Experienced with PEG/RBV, Non-Cirrhotic 1 Epclusa 100% 12 $76, I A 2 Technivie & Ribavirin 100% 12 $75, I A 3 Mavyret 93% 8 $31, I B 4 Harvoni 95% 12 $96, IIa B 5 Zepatier 87% 12 $55, IIa B 6 Zepatier & Ribavirin 87% 16 $74, IIa B Preferences were based on level of evidence to comply with DHCS policy, SVR-12, pill burden, and adverse effects. Technivie and Zepatier have increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning treatment. The package inserts also clearly state that Technivie and Zepatier are contraindicated for use in CTP class B or C, hence Technivie in this treatment group can be initiated if the patient is non-cirrhotic/ctp class A. Vigilance in evaluating contraindications for each individual agent is necessary in ensuring the safety of patients taking HCV regimens. Coverage Policy Infectious Diseases - Hepatitis C Page 18

19 Genotype 4, Treatment Experienced with PEG/RBV, Compensated Cirrhotic 1 Epclusa 100% 12 $76, I A 2 Technivie & Ribavirin % 12 $75, I A 3 Mavyret 100% 12 $47, IIa B 4 Harvoni & Ribavirin 94% 12 $96, IIa B 5 Zepatier 87% 12 $55, IIa B 6 Zepatier 87% 16 $74, IIa B Preferences were based on level of evidence to comply with DHCS policy, SVR-12, and overall cost. Technivie with ribavirin has the most concrete evidence supporting its use in genotype 4, treatment experienced, noncirrhotic patients. The outcome of serious liver injury with Technivie was reported mainly in patients with evidence of advanced cirrhosis prior to initiating the medication. Technivie and Zepatier have increased risk of liver injury, but these outcomes were reported mainly in patients with evidence of advanced cirrhosis prior to beginning treatment. The package inserts also clearly state that Technivie and Zepatier are contraindicated for use in CTP class B or C, hence Technivie in this treatment group can be initiated if the patient is noncirrhotic/ctp class A. Vigilance in evaluating contraindications for each individual agent is necessary in ensuring the safety of patients taking HCV regimens. Genotype 4, Treatment Experienced with NS5A Inhibitor, Regardless of Cirrhosis 1 Vosevi 96% 12 $89, I A There is currently only one option available for this treatment group. Genotype 5 or 6, Treatment Naïve, Regardless of cirrhosis 1 Mavyret 100% 8 or 12 $31, or $47, I A 2 Epclusa % 12 $76, I B 3 Harvoni 95-96% 12 $96, IIa B Genotype 5 or 6, Treatment Experienced with PEG/RBV, Regardless of cirrhosis 1 Mavyret 100% 12 $47, I B 1 * Mavyret 100% 8 $31, IIa B 2 Epclusa 100% 12 $76, I A 3 Harvoni 100% 12 $96, IIa C Genotype 5 or 6, DAA Treatment Experienced (Includes NS5A inhibitor), Regardless of cirrhosis 1 Vosevi 100% 12 $89, IIa B For patient s that have cirrhosis *For patient s without cirrhosis Justification for Genotypes 5 & 6, regardless of treatment history and cirrhosis status: There is very limited data on both regimens in either genotype 5 or 6. Preferences were based on level of evidence to comply with DHCS policy, SVR-12, and overall cost. Coverage Policy Infectious Diseases - Hepatitis C Page 19

20 Decompensated Cirrhosis, Genotype 1, 4, 5, or 6, Regardless of Treatment History 1 Epclusa & Ribavirin 94-96% 12 $76, I A 2 Harvoni & Ribavirin 87% 12 $96, I A 3 b Epclusa 86-92% 24 $156, I A 4 b Harvoni 89% 24 $192, I A 5 Daklinza & Sovaldi & Ribavirin 83% 12 $145, I B 6 a Epclusa & Ribavirin 97% 24 $156, II C 7 a Harvoni & Ribavirin 89% 24 $192, II C 8 b Daklinza & Sovaldi 89% 24 $290, II C Decompensated Cirrhosis, Genotype 2 or 3, Regardless of Treatment History 1 Epclusa & Ribavirin % 12 $76, I A 2 b Epclusa % 24 $156, I A 3 Daklinza & Sovaldi & Ribavirin 83% 12 $145, II B 4 b Daklinza & Sovaldi 83% 24 $290, II C 5 a Epclusa & Ribavirin - 24 $156, II C a Corresponds to persons treatment experienced with Sovaldi b Ribavirin ineligible Treatment regimens for decompensated cirrhotic patients were first arranged based on the corresponding level of evidence to comply with DHCS Policy, then by SVR-12 and overall cost. Note that Sovaldi with Ribavirin in Genotype 2 or 3 decompensated cirrhotic patients and is no longer recommended. There is no outcome data for decompensated patients with history of Sofosbuvir failure. The recommended regimen is based off compensated cirrhotic patients. Post-Liver Transplantation, Genotype 1, 4, 5, or 6, Regardless of Treatment History, Infection in Allograft, Includes those with Compensated Cirrhosis 1 Mavyret 98% 12 $47, I A 2 Harvoni & Ribavirin 96% 12 $96, I A 3 Daklinza & Sovaldi & Ribavirin 87-94% 12 $145, I B 4 Olysio & Sovaldi & Ribavirin 92%* 12 $148, I B 5 Olysio & Sovaldi 92%* 12 $148, I B Post-Liver Transplantation, Genotype 2 or 3, Regardless of Treatment History, Infection in Allograft, Includes those with Compensated Cirrhosis 1 Mavyret 98% 12 $47, I A 2 Daklinza & Sovaldi & 87-94% 12 $145, II A Ribavirin 3 Mavyret - 12 $47, II C 4 Epclusa & Ribavirin - 12 $76, II C *SVR-4 based on a retrospective multicenter analysis For patient s without cirrhosis Treatment regimens for decompensated cirrhotic patients were first arranged based on the corresponding level of evidence to comply with DHCS Policy, then by SVR-12 and overall cost. Coverage Policy Infectious Diseases - Hepatitis C Page 20

21 Post-Liver Transplantation/Decompensated Cirrhosis, Genotype 1, 4, 5 or 6, Regardless of Treatment History 1 Harvoni & Ribavirin 60-85% 12 $96, I B Post-Liver Transplantation/Decompensated Cirrhosis, Genotype 2or 3, Regardless of Treatment History 1 Daklinza & Sovaldi & Ribavirin 83-91% 12 $145, II A 2 Epclusa & Ribavirin - 12 $76, II C There is very little evidence overall for patients within these treatment groups. As these are the only currently listed recommendations per AASLD, any other treatment regimens will be considered investigational and evaluated on a case-by-case basis per the criteria for coverage of Investigational Services (Title ). REFERENCES 1. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to Ann Intern Med. 2014;160(5): Denniston MM, Klevens RM, McQuillan GM, Jiles RB. Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey Hepatology. 2012;55(6): Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during MMWR Recomm Rep. 2012;61(RR-4): Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5 Pt 1): DHCS Treatment Policy for the Management of Chronic Hepatitis C. California Department of Health Care Services Web Site. Updated July 1, Accessed September 1, Adapted from the American College of Cardiology and the American Heart Association Practice Guidelines. (American Heart Association, 2011) 7. FDA. What is a Serious Adverse Event. FDA Safety Jan. Accessed September 1, HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America Web Site. Updated April 12, Accessed May 2, Copegus [prescribing information]. South San Francisco, CA: Hoffmann-La Roche, Inc. c/o Genentech, Inc; Pegasys [prescribing information]. Kenilworth, NJ: Schering Corporation; Incivek [prescribing information]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; Victrelis [prescribing information]. Whitehouse Station, NJ: Schering Corporation; Olysio [prescribing information]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; Sovaldi [prescribing information]. Foster City, CA: Gilead Sciences, Inc; Viekira Pak [prescribing information]. North Chicago, IL: AbbVie Inc; Harvoni [prescribing information]. Foster City, CA: Gilead Sciences, Inc; Technivie [prescribing information]. North Chicago, IL: AbbVie Inc; Daklinza [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; Yee HS, Chang MF, Pocha C, et al. Update on the Management and Treatment of Hepatitis C Virus Infection: Recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol May;107(5): Poordad F, Lawitz E, Reddy KR, et al. Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection--a randomized trial. Gastroenterology. 2013;145(5): Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbopoietin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361: [TREAT] 22. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355: [CHOIR] 23. Epogen [prescribing information]. Thousand Oaks, CA: Amgen Inc; Aranesp [prescribing information]. Thousand Oaks, CA: Amgen Inc; Coverage Policy Infectious Diseases - Hepatitis C Page 21